ABSTRACT This application is for a Mentored Clinical Scientist Research Career Development Award (K08) for Dr. Kevin Byrd. He is currently conducting research into the role of mitotic spindle orientation in oral epithelial development and has observed that during oral mucosal epithelial development, perpendicular divisions become more numerous and are essential for differentiation. This K08 will allow Dr. Byrd to 1) become an expert in oral epithelial differentiation through molecular regulation of mitotic spindle positioning, 2) to conduct basic science research in vivo in a tissue rarely studied, 3) to gain the skills to utilize ex vivo organotypic models to describe this phenomenon in human oral epithelial differentiation, 4) to gain the skills necessary to collaborate and to perform ?-omics? approaches in oral epithelial stem cell identification, and 5) to develop an independent science research career that will allow him to ask questions in collaboration with clinical and basic scientists. A multidisciplinary team of experts have agreed to provide invaluable support to him upon funding of this application: 1) Drs. Eric Everett (basic science; dental research), Susan Henning (basic science; gastrointestinal research), Steven Offenbacher (translational and clinical science, dental research, and Dr. Ophir Klein (clinician-scientist: GI and dental stem cells), 2) research training by epithelia and oral biology experts: primary mentor, Dr. Scott Williams and co-mentor, Dr. Jennifer Webster-Cyriaque, and 3) RNA-seq and bioinformatics training: (Drs. Piotr Mieczkowski, Scott Magness, and Di Wu). These mentors and the training they make available will provide him with the skills to become a successful, independent investigator. The paucity of oral epithelial mouse models has resulted in minimal characterization of oral epithelial differentiation networks, and a poor understanding of oral epithelial stem cells and their niches. Based on his rapid generation (8-12 weeks total) of an oral epithelia mouse model, Dr. Byrd has already shown that the mitotic spindle orientation gene LGN (Gpsm2) is essential in promoting differentiation and tissue patterning in the oral cavity. The pace and specificity in which he can generate new oral epithelial mouse models where few exist?weeks as opposed to months or years?is unprecedented compared to traditional methods. Dr. Byrd's research will focus on oral epithelial differentiation, which is critical in understanding how the oral cavity heals in response to injury. This project will create three novel, oral epithelial mouse models and surrogate ex vivo human models to assess the role of oriented cell divisions in oral epithelial differentiation (Aim 1 and 2), and will utilize a unbiased, genetic label retaining cell model to identify and profile quiescent cells from oral basal epithelial cells (Aim 3). Dr. Byrd's research will inform the basis of a future project on reserve stem cell function in oral epithelial wound healing, to be proposed in the last year of the funding period (K99/R00).